A Life in NMR: Interview with Regina Schuck, VP and General Manager of Agilent Research Products Division

Education Article

Published: Jul 1, 2014

Channels: MRI Spectroscopy / NMR Knowledge Base

Regina Schuck is general manager of Agilent's Research Products Division, formerly Varian Inc, and Vice President.

Her organization provides solutions for the life science markets which include genomics, proteomics, research and disease understanding, and pharmaceutical drug discovery and development/QA/QC. She has product development responsibility for NMR spectrometry, pre-clinical MRI and single crystal X-ray diffraction systems.

Regina Schuck joined Agilent through the Varian Acquisiton. At Varian she held various positions within the Research Products Business; most recently as General Manager for Magnetic Resonance Business. She has 25 years of experience within NMR and research MRI.

Regina holds a PhD in Natural Sciences and a Diploma in Chemistry from the University of Frankfurt, Germany.

In your opinion, what has been the most significant development in NMR research since you first began working in the field?

I am lucky to have been working in NMR, which has been a very dynamic and exciting research area, over the past few decades. This of course means that there are a significant number of enabling developments that have either expanded applications for nuclear magnetic resonance or greatly improved the efficiency of the technique. Two that come immediately to mind are the development of pulse field gradients (PFG) and the invention of cryogenic probe technology.

Pulsed Field Gradient pulses (pulses with spatial dependent field intensity) became routine around 20 years ago. PFG's enable convenient and non invasive means of measuring translational motion as well as an elegant way for researchers to "manipulate" spin coherence, thus making them essential for shimming (magnet homogeneity optimisation), solvent suppression, coherence pathway selection in complex NMR experiments and diffusion measurements.

Cryogenic probe technology is also high on my list, since it addresses the fundamental weakness of NMR - low sensitivity as compared to other spectroscopic methods. The 3-5x gain in sensitivity that cold probes offer has enabled previously established methods to be applied for analysis of a wider diversity of samples and for a broader range of applications.

Over your career in research, with which developments have you been most proud to be involved?

It has been rewarding to see how advances in technology and methods development have come together enabling complete systems that address a wide diversity of scientific problems. The power of NMR to "visualise" how molecules interact, in the context of molecules dynamics and three dimensional structure makes it unique for studying the mechanistic and functional properties of proteins and nucleic acids. When I look at the contribution NMR has made to the study of structural biology, I am very proud of the fact that our company was a pioneer in the development and commercialisation of technology that has led to significant advances in areas such as cancer research.

Have the customer base and client requirements for NMR changed over the time that you have been working in research and development?

"The power of NMR to 'visualise' how molecules interact, in the context of molecules dynamics and three dimensional structure makes it unique for studying the mechanistic and functional properties of proteins and nucleic acids."

Absolutely. NMR has migrated from being a specialty tool to one that is used on a routine basis by a broad set of customers. For example, virtually every Pharmaceutical company's medicinal chemistry department now utilises NMR as a tool to verify the structure of small molecule compounds. Their needs have driven innovation across the entire experimental workflow ranging from improvements in automated sample handling to easy to use software that automatically delivers results on an individual chemist's desktop computer.

What current developments are you most excited by at the moment?

For the past eight years we've been working on technology to shorten the amount of time it takes to solve structures via NMR (so called Fast Methods). Recent advances in probe design, signal receiver hardware configuration and pulse sequence design are reducing the time it takes to record multi-dimensional NMR experiments and thus solve structures via NMR (or indeed obtain any other information, such as molecular dynamics, chemical exchange, molecular binding, screening, etc.) much faster. Many of these new methods involve the parallel acquisition of spectra via multiple receivers for both small molecules and macromolecules.

One of the most surprising and provocative future directions for our research is a potential new paradigm where the NMR spectrometer makes choices about operating parameters based on measurements that it is currently recording. This concept could ultimately lead to an operating mode where unsupervised NMR investigations are carried out based on artificial intelligence approaches.

In the podcast interview (Download MP3; 10.6MB), you mentioned several advantages of NMR over other techniques - is lack of sensitivity the main barrier to NMR being used more widely, or are there other issues to be considered (e.g., time, cost, equipment/training requirements)?

Although NMR is certainly 'sensitivity challenged' as compared to a number of other analytical techniques, it remains a unique and powerful tool for the determination of molecular structure and dynamics. I'm confident that continued developments on the technology front will improve measurement sensitivity. That said, in order for NMR to become a standard analytical technique that can be utilised by a much broader set of scientists, there are additional challenges that must be overcome. These include the size and cost of the instrumentation, maintenance requirements (frequent cryogen fills) and the relatively high level of training required to become proficient with the technique. We're thinking broadly about these issues and investing in a number of new technologies that have the potential to adapt the technique for a much broader set of users.

As NMR sensitivity continues to improve, in what areas do you see NMR becoming the analysis method of choice over other more traditional spectroscopic techniques?

"Recent advances in probe design, signal receiver hardware configuration and pulse sequence design are reducing the time it takes to record multi-dimensional NMR experiments and thus solve structures via NMR much faster."

NMR has several important advantages as compared to other traditional methods. Generally speaking, there is no sample preparation required to run the analysis. This saves considerable time and effort, especially when working with large numbers of samples. In addition, the technique is quantitative. Calibration is easy and straightforward, delivering accurate and precise results. This combination makes NMR an ideal tool for complex mixture analysis or routine identification of impurities in process development and production environments.

If NMR sensitivity was improved to the level of other traditional techniques, are there techniques that would rapidly become obsolete?

As mentioned above, NMR as a technique has some unique attributes. Improvements in sensitivity and ease of use will increase the applicability of the method, especially in situations where customers have limited amounts of sample. We don't see NMR replacing other techniques; rather complementing them with additional information about the structural and dynamic properties of molecules. Enhanced sensitivity coupled with reduced cost (capital and operational) and enhanced ease of use should enable NMR to be utilised by a much broader set of customers than can access it today.

Is research ongoing in the development of dynamic nuclear polarization for practical purposes, or has its further development been abandoned despite its large potential?

We have already touched base on the importance of sensitivity for NMR. There is no question that the DNP methodology is exciting through its promise to deliver a very significant sensitivity gain. It is a method that we have been discussing with key thought-leaders in the community and also extensively evaluated internally. We recognise its potential but are also keenly aware of the significant technical hurdles that have to be overcome to make it a practical and generally applicable method even within solid state NMR.

Staying of the forefront of technology development is a key for us. In the case of DNP development, we believe the most productive approach to bringing this technology to our cutting edge, development focused customers, was through partnering. At the ENC conference this spring we have announced Collaboration with Bridge12. Under the agreement, Bridge12 will provide critical terahertz components such as gyrotrons and terahertz transmission lines for DNP-NMR to be integrated with our new and existing spectrometers.

In your podcast, you mentioned that development of the NMR consoles and system was a focus of your current research - are you able to expand on the mechanism by which improvements in these features would increase sensitivity?

Our objective is to build systems that will enable our customers to achieve optimal experimental performance across a diverse set of applications. This requires us to think simultaneously about the design and performance aspects of individual components (e.g., magnet, console, probes) and the overall system. We are investing on all of these fronts. Now that we're part of Agilent, we have access to talent and technologies that simply weren't available to us before. More specifically, we intend to leverage Agilent's Electronic Measurement Group to help us design next generation console and probe technology that will deliver better overall performance as measured in terms of system stability, sensitivity, and ease of use.

Do you feel that sensitivity improvement in established techniques is the key driver of research, or are there additional applications of NMR still to be addressed, for which novel techniques will need to be developed?

NMR researchers continue to surprise the scientific community with the development of new applications and novel techniques. Of course, these developments are often complemented and sometimes enabled by breakthroughs on the technology front.

Examples include:

Diffusion Ordered Spectroscopy (DOSY) for the analysis of complex mixtures - linked to improvements in gradient strength and linearity

I expect this 'virtuous circle' to continue driven by parallel and synergistic advances in both new technology and novel experimental techniques/methods.

How has the advent of multi-dimensional NMR impacted the field? What are the particular applications and advantages for this technique?

The fact that the 1991 Nobel Prize in Chemistry was awarded in part for the two-dimensional (2D) NMR experiments speaks to the tremendous importance of multi-dimensional NMR techniques. Once 2D NMR methods were developed, 3D came along reasonably soon and now researchers are starting to use even 5D methods.

NMR is a very powerful spectroscopic technique, due to its incredible "sensitivity" to even the smallest details of chemical structure as well as to secondary structure and to its capability to detect interaction between protons that might be at different ends of a molecule but are close in space. However, a lot of this information in NMR manifests itself as peaks of slightly different frequencies and as peaks with different multiplicity structure. When a chemist records the 1 dimensional NMR structure of a molecule, they get a peak for each proton atom in the molecule, but often the peaks are split into several lines depending on the number of neighboring atoms. There is incredible amount of information in this 1D peak list, but as molecules get bigger the peaks start to overlap and information gets lost. Multi-dimensional NMR methods spread the NMR information from a single list of peaks into multiple dimensions and thus significantly enhance resolution. The development of the first 2D methods have by flourished into practically thousands of NMR pulse sequences that look at the connectivity of different atoms, and thus allow the complete mapping of the chemical backbone and structure of molecules.

Multi-dimensional NMR methods are now routine and our software enables chemists and biologists to set up and optimise them with just with a few mouse clicks.

Do you see combined techniques (such as LC/MS-NMR) becoming more prevalent in the field? If so, are research departments working in increasingly multidisciplinary teams or are researchers acquiring additional skill-sets to accommodate these changes?

Hyphenated techniques such as LC-NMR and LC/MS-NMR certainly have application in the analytical world. For example, LC/NMR has the capability to distinguish between isomers, whether structural, conformational or optical. Also, as compared to many other analytical techniques, the method is non-destructive so fractions can be recovered for later analysis.

The decision about whether to use these techniques in an integrated manner or run them side by side depends on the type of information that the user is trying to gather and the sample types available for analysis. But these techniques are complex to implement and often suffer from incompatible matrices.

Because Agilent has expertise in liquid chromatography, mass spectrometry and nuclear magnetic resonance, we have the opportunity to design and build next-generation integrated systems. Alternatively, there are also opportunities to leverage software tools to leverage individual data sets generated from distinct analytical methods. We have designs on both.

Is your research department a self-sufficient team or do you work and have active collaborations with other research teams and institutions?

"One can envision a future state where the spectrometer will be driven by artificial intelligence algorithms that will be capable of choosing the right experiments executed in the right sequence to automatically determine the structural and dynamic properties the researcher is seeking."

Agilent has a long history of technology innovation implemented through a combination of internal and external investments. In addition to our own R&D group, the company has a function called Agilent Laboratories. Their mission is to look beyond the normal product development horizon, typically 3-5 years out. We are actively working with the Labs group and happy to have access to these additional resources as part of Agilent.

Agilent also has an active University Relations program which funds collaborative development projects with academic researchers. Several of our customers have already received grants to pursue interesting ideas that will ultimately expand the boundaries of what's possible with NMR.

How important is cross-communication and idea-sharing with other researchers in your field?

Very important! Our job is to provide the best possible tool set for our customers. We can only do that if we're in touch with our customers on a regular basis. Meetings and conferences are a great venue for this type of interaction, and we've recently introduced a web forum call spinsights.net to share ideas and seek customer input.

In what direction do you see the research field heading currently and where do you see the field in 50 years' time?

One can envision a future state where the spectrometer will be driven by artificial intelligence algorithms that will be capable of choosing the right experiments executed in the right sequence to automatically determine the structural and dynamic properties the researcher is seeking. Although this might be possible for both small molecules and macromolecules, we think it's likely that these will be implemented first for small molecule applications. An extension of this idea is a bench top NMR system that can be utilised in the chemistry lab for a limited but routine set of applications such as small molecule structure confirmation.

On the Bio front, we are starting to see NMR techniques applied for the analysis of new and interesting therapeutic targets. These include membrane bound proteins and nucleic acids. As technology continues to advance, NMR data could become part of the standard tool kit that drug discovery groups use as part of a 'virtual' drug discovery process.

What do you feel are the largest hurdles to be overcome in the development of new NMR technology?

In both magnet and probe technology new materials must be employed to enable further breakthroughs in NMR performance. This most likely means application of high temperature superconductors - most likely the cuprate materials such as YBCO and BSCCO. These new materials are essential to build superconducting magnets above the 1GHz range, and for the next generation of cold probes. Although these materials have been under intensive study for more than 20 years, we are now getting close to the point where routine commercial applications are possible.

What do you think is the next big development that will impact the field of research?

I hope that my answers to the previous questions have established that over the past decades it was not a single development, but a strong combination on technology and methodology development that has shaped the field of NMR research. I truly believe that this is a trend that will stay with NMR for decades to come. This is exactly the reason why as instrument manufacturers we need to stay very closely connected with the scientific community and work together with our thought-leaders. I expect combinations of developments to make the next significant impact, not a single big thing. For example, as sensitivity and resolution are enhanced, NMR instrumentation needs to deliver the speed & stability to measure smaller and smaller effects. We often look to leaders in the community to provide input on where they believe NMR be applied next, and they never stop amazing us with their ideas.